The present invention relates to novel substituted tetrazoles and derivatives thereof useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. More particularly, the novel compounds of the present invention act at muscarinic receptors and may be useful in treating the symptoms of cognitive decline in an elderly patient.
Disorders of cognition are generally characterized by symptoms of forgetfulness, confusion, memory loss, attentional deficits and/or, in some cases, affective disturbances. These symptoms may arise as a result of the general aging process and/or from organic brain disease, cerebrovascular disease, head injury or developmental or genetic defects.
The general decrease in cognitive function which accompanies the aging process is well accepted. The same phenomenon has been observed and documented in many lower mammals, including those routinely employed in pharmacological testing programs for screening and predicting usefulness for particular drugs in higher animals, including humans.
Although disorders of cognition often accompany the general aging process, presenile and senile primary degenerative dementia are the most common accepted causes of mental deterioration in the elderly. It has been estimated that at least ten percent of persons over sixty years of age will eventually suffer severe mental deterioration. A much larger number will experience cognitive decline of sufficient severity to impede their activities.
Many of the symptoms of cognitive disorders, especially impaired memory, are associated with decreased acetylcholine synthesis and the impairment of cholinoreceptive neurons. In the hippocampus and cerebral cortex of patients suffering from primary degenerative dementia for example, the level of the enzyme choline acetyltransferase (CAT) can be reduced as much as ninety percent (see Davies, P., et al, The Lancet, 2, page 1403 (1976); Perry, E. K., et al, Journal of Neurological Sciences, 34, pages 247-265 (1977); and White, P., et al, The Lancet, 1, pages 668-670 (1977)).
Since CAT catalyzes the synthesis of acetylcholine from its precursors choline and acetyl coenzyme A, the loss of CAT reflects the loss of cholinergic or acetylcholine-releasing nerve endings in the hippocampus and cerebral cortex. There is abundant evidence that cholinergic terminals in the hippocampus are critically important for memory formation.
The cholinergic hypothesis suggests that drugs which restore acetylcholine levels or cholinergic function (i.e., cholinomimetic) are effective in correcting this deficit in neurotransmitter chemical and provide treatment of the memory impairment symptom of cerebral insufficiency. Considerable biochemical, pharmacological, and electrophysiological evidence supports the hypothesis that deficits in the cholinergic system underlie geriatric cognitive dysfunction (Peterson, C. and Gibson, G. E., Neurobiology of Aging, 4, pages 25-30 (1983)). Aged humans and nonhuman primates with decreased cognition show improved memory when they are treated, for example, with acetylcholinesterase inhibitors such as physostigmine. These agents increase the available supply of synaptic acetylcholine by inhibiting its hydrolysis.
Aminopyridines such as 3,4-diaminopyridine ameliorate age-related cognitive deficits by increasing the release of acetylcholine from presynaptic nerve terminals, thus increasing synaptic acetylcholine (see Davis, H. P., et al, Experimental Aging Research, 9, pages 211-214 (1983)).
It has been known for some time that the natural alkaloid, muscarine, has the ability to act relatively selectively at autonomic effector cells to produce qualitatively the same effect as acetylcholine. Two other agents, pilocarpine and oxotremorine, have the same principal sites of action as muscarine and acetylcholine and are thus classified as having "muscarinic" action.
It is well known that the cholinergic hypothesis suggests that cholinomimetics, including muscarinic agents, may have potential in treating senile cognitive decline (SCD). However, the multiple development issues associated with cholinomimetics, including, for example, poor bioavailability, short duration of action, and especially parasympathetic side effects, have diminished hopes of adequate therapy with this class of agents.
A series of fused imidazole compounds represented by the formula ##STR1## wherein A is lower alkylene,
R.sup.1 is hydrogen, lower alkyl, lower alkoxy or halogen, PA1 R.sup.2 is hydrogen, lower alkyl, cyclo(lower)alkyl, pyridyl, ar(lower)alkyl which may be substituted with halogen, or aryl which may be substituted with lower alkyl, lower alkoxy, hydroxy or halogen, PA1 R.sup.3 is N-containing unsaturated heterocyclic group which may be substituted with lower alkyl or amino, and PA1 Y is .dbd.C-- or .dbd.N-- useful as antiulcer agents is disclosed in U.S. Pat. No. 4,563,455.
A series of heterocyclic compounds represented by the formula where the dotted line designates an optional bond ##STR2## wherein "het" designates a five-membered heterocyclic ring which may include one or two double bonds and one to four heteroatoms selected from nitrogen, oxygen or sulphur, provided that "het" may not designate a 1,2,4- or 1,3,4-oxadiazole;
R.sup.1 is selected from hydrogen, lower alkyl optionally substituted with phenyl which may be substituted with halogen, lower alkyl, or lower alkoxy, or a group R.sup.6 --CO--NH--CH.sub.2 -- or R.sup.6 --O--CO-- where R.sup.6 is lower alkyl, branched or unbranched, or phenyl optionally substituted with halogen, trifluoromethyl, lower alkyl, hydroxy, lower alkoxy, or lower acyloxy;
R.sup.2 and R.sup.3 are the same or different, each representing hydrogen, lower alkyl, cycloalkyl (three to six carbon atoms), lower alkenyl, lower alkadienyl, lower alkynyl, optionally substituted with hydroxy, halogen, or phenyl in which the phenyl group may be substituted with halogen, trifluoromethyl, lower alkyl, hydroxy or lower alkoxy; R.sup.2 and R.sup.3 may further, respectively, be selected from trifluoromethyl or phenyl optionally substituted with halogen, trifluoromethyl, lower alkyl, hydroxy, lower alkoxy, or lower acyloxy, or R.sup.2 and R.sup.3 may, respectively, be a group OR.sup.7 or SR.sup.7 where R.sup.7 is defined as R.sup.2 or R.sup.3, and if "het" includes two or more carbon atoms,
R.sup.4 and R.sup.5 are the same or different, and each is defined as R.sup.2 or R.sup.3 and
if "het" includes only one carbon atom, there is only one substituent, R.sup.4, on the heterocyclic ring, and R.sup.4 is defined as R.sup.2 or R.sup.3,
as well as individual stereoisomers and pharmaceutically acceptable acid addition salts thereof useful for the treatment of disorders caused by malfunction of the acetylcholine or muscarinic system is disclosed in European Patent Application 0296721.
A series of substituted tetrazoles of the formula ##STR3## wherein R.sup.1 is .beta.-naphthyl, .alpha.-naphthyl, .alpha.-pyridyl or phenylethyl and R.sup.2 is CH.sub.3 --, CF.sub.3 --, (CH.sub.3).sub.2 CH--, trans--CH.sub.3 --CH.dbd.CH-- or trans,trans--CH.sub.3 --CH.dbd.CH--CH.dbd.CH-- is disclosed by Zbiral, E. and Stroh, J., Liebigs Annalen der Chemie, 725, pages 29-36 (1969).
3(5)-Tetrazolyl-(1)]-pyrazole is disclosed by Reimlinzer, H., et al, Chemische Berichte, 103, pages 2821-2827 (1970).
However, none of the compounds disclosed in the aforementioned references suggest the combination of structural variations of the compounds of the present invention described hereinafter. Furthermore, the aforementioned compounds are not disclosed for treating the symptoms of cognitive decline in an elderly patient.
The substituted tetrazoles and derivatives thereof of the present invention may have affinity for the muscarinic receptor and thus are expected to be useful in the treatment of the symptoms of cognitive decline in an elderly patient including Alzheimer's disease.